AB038. NGS-based diagnostics for genetic disorders—promises and pitfalls

Abstract: Genetic testing forms an integral part of clinical management of heritable genetic disorders as it provides options for molecular diagnosis, carrier identification, prenatal diagnosis, etc. The impetus for the development of diagnostic assays for genetic testing of a disease is often influenced by how much is known about its molecular basis, its incidence among the local population and the clinical demand for testing. Subsequent laboratory implementation of a research test for clinical diagnostic testing requires demonstration of clinical utility and validity. Next-generation sequencing (NGS) approaches are increasingly being adopted for clinical diagnostics as the costs becomes increasingly affordable and its utility to resolve diagnostic odysseys has brought resolutions to many families. Validation of such NGS assays is complex but follows similar established guidelines as for traditional genetic tests. There is high analytical sensitivity for most of these assays although the true clinical sensitivity may remain unknown for some disorders. Targeted analysis using NGS is now available for many gene panels, e.g., involving myopathies, cilipathies, cardiomyopathies, etc. as well as for single gene disorders such as Wilson disease, retinoblastoma, RYR1-related diseases, etc. As the costs for sequencing whole exomes and genomes progressively drop further, it is anticipated that these technologies will also begin to transit into the clinical realm. This talk discusses the impact and challenges of NGS in clinical testing and the diagnostic dilemmas in test interpretations for these lab tests.

Keywords: Next-generation sequencing (NGS); genetic testing; heritable genetic disorders